This article is Nouable Magazine.
Looking through a microscope in 1910, French-Canadian microbiologist Félix d’Hérel noticed “clear spots” in bacterial cultures that turned out to be viruses that preyed on bacteria. A few years later, d’Hérel would coin the term “viruses” to describe these viruses. BacteriophageIt was founded after World War I to treat patients suffering from dysentery.
Over the next few decades, d’Hérelle and his colleagues used phage therapy to treat bubonic plague and cholera, but the technique fell out of use after antibiotics became widely adopted in the 1940s.
But now, as bacteria develop resistance to a growing number of antibiotics, researchers are rediscovering phage therapy, sometimes with a novel twist: rather than simply using phages to kill bacteria directly, new strategies aim to exploit the evolutionary dilemma that bacteria face when they cannot simultaneously evade phages and antibiotics.
The plan, which uses a technique called “phage steering,” has shown promising results in early tests, but the extent of its usefulness is yet to be proven.
We certainly need to find new ways to combat bacterial infections. 70% of hospital-acquired bacterial infections in the United States Resistant to at least one antibiotic. Acinetobacter, Pseudomonas, E. coliand KlebsiellaIt is classified by the World Health Organization as the greatest threat to human health. Multiple antibioticsIn 2019, antibiotic resistance 4.95 million deaths worldwideThere is a growing demand for more effective treatments.
One way bacteria develop resistance to antibiotics is by exploiting membrane structures designed to pump unwanted molecules out of the cell. By modifying these “efflux pumps” to recognise antibiotics, bacteria can eliminate the drugs before they can poison them.
As it turns out, some phages appear to use the same efflux pumps to invade bacterial cells. The phage is thought to attach its tail to the outer part of the pump protein, like a key slipping into a lock, and then inject its genetic material into the cell. This happy coincidence led Yale evolutionary biologist Paul Turner to suggest that treating patients with phages and antibiotics simultaneously could put the bacteria in a no-win situation: if the bacteria modified their efflux pumps so that the phage could no longer bind, the pumps would no longer pump out the antibiotic, and the bacteria would lose resistance. But if the bacteria maintained antibiotic resistance, The phage will kill them.As Turner and colleagues explained in 2023: Annual Review of Virology.
In other words, the result is a double attack, says Michael Hochberg, an evolutionary biologist at the French National Center for Scientific Research who studies ways to prevent the evolution of bacterial resistance. “It’s kind of like a cross effect.” The same principle could be used to target other bacterial molecules that play dual roles in viral and antibiotic resistance.
Turner tested this hypothesis with multidrug-resistant strains. Pseudomonas aeruginosaThis bacterium has four efflux pumps that are involved in antibiotic resistance, and Turner predicted that if he could find a phage that uses one of the pumps as a way into the cell, the bacterium would be forced to mutate the receptor to close the door on the phage, hindering its ability to expel the antibiotic.
Turner’s team collected samples from the environment and collected 42 infectious phage isolates. Pseudomonas aeruginosaOf all the phages, OMKO1 bound to the efflux pump and was the best candidate for our experiments.
The researchers then cultured the antibiotic-resistant bacteria. Pseudomonas aeruginosa Working with OMKO1, the researchers hoped to force the bacteria to modify their efflux pumps to resist the phages. They exposed these phage-resistant bacteria, as well as normal phage-susceptible bacteria, to four antibiotics to which the bacteria are resistant: tetracycline, erythromycin, ciprofloxacin, and ceftazidime.
As the theory predicted, bacteria that developed resistance to phages were more sensitive to antibiotics than bacteria that had not been exposed to phages, suggesting that the need to fight phages forced bacteria to lose antibiotic resistance.
Other researchers have also shown that phage steering can restore susceptibility to common antibiotics to which bacteria have become resistant. In one study by an international team, a phage called Phab24 Restores susceptibility to the antibiotic colistin in Acinetobacter baumanniiwhich can cause life-threatening illness.
In the second study, researchers from Monash University in Australia collected infectious bacteria from patients and A. Baumani Bacteria exposed to ΦFG02 and ΦCO01 phages The gene was inactivated It helps form the microbe’s vital outer layer, or capsule. This layer acts as an entry point for phages, but it also helps form the biofilm that keeps antibiotics at bay. So removing this layer A. Baumani They are now sensitive to some antibiotics to which they were previously resistant.
In the third study, British researchers Pseudomonas aeruginosaStrains that are resistant to all antibiotics Bacteria exposed to the phages became susceptible to two antibiotics that had previously been thought to be ineffective. Pseudomonas aeruginosa .
Turner’s team has used phage steering to personalize treatments in dozens of cases in the clinic, says Yale microbiologist Benjamin Chang, who collaborates with Turner. Chang says many of the unpublished results are promising so far. Non-respiratory infections are relatively easy to cure, and even lung infections that phage steering cannot hope to eradicate completely often show some improvement. “We’ve been pretty successful in using phage steering to treat infections that are difficult to manage, and in many cases we’ve seen a reduction in antibiotic resistance,” he says. But Chang notes that it can be hard to tell if phage steering has truly led to a cure.
Graham Hatfull, a molecular biologist at the University of Pittsburgh, says phage therapy won’t work on all antibiotic-resistant bacteria because phages are highly host-specific, and no one knows which targets on the bacterial cell surface most phages will bind to. For phage induction to counteract antibiotic resistance, the phage needs to bind to a molecule involved in that resistance, but it’s not clear how often that coincidence occurs.
Jason Gill, who studies bacteriophage biology at Texas A&M University, says it’s not easy to predict whether a phage will induce susceptibility to an antibiotic, so you have to look for the right virus every time.
Gill knows from experience how complicated this approach can be: He was part of a team of researchers and doctors who used phages to treat patients with multidrug-resistant bacteria. A. Baumani Infection. Within four days of the team administering the phages intravenously and through the skin, the patient woke up from a coma and began to respond to the antibiotic minocycline, which had previously been ineffective against him. It was a stunning success.
But when Gill tried a similar experiment in cell cultures, he got different results. A. BaumaniThe bacteria developed resistance to the phages but also maintained resistance to minocycline. “The mechanism is not fully understood,” Gill says. “The relationship between phage resistance and antibiotic susceptibility is likely to vary across bacterial strains, phages, and antibiotics.” That means phage steering doesn’t always work, Gill says.
Turner points out another potential problem: phages could be too effective. For example, if phage therapy kills so many bacteria that their remains are rapidly deposited in the bloodstream, they could cause septic shock in the patient. Scientists haven’t yet fully figured out how to solve this problem.
Another concern is that doctors can’t control phages as tightly as they can antibiotics. “Phages mutate, they adapt, and they have genomes,” Hochberg says. Safety concerns are one reason that countries like the United States have prevented the routine use of phage therapy, limiting it to case-by-case applications like Turner and Chang’s, he said.
Phage therapy may have been too high-tech for the 1940s, and even today scientists struggle to use it. Turner says what’s needed now are rigorous experiments that can tell us how to make phage therapy work.
